PROJECT SUMMARY/ABSTRACT Melanoma has a high propensity for metastasis and accounts for 80% of skin cancer-related deaths. Despite the progress in melanoma therapeutics over the last several years, melanoma remains a challenge in clinical oncology. The immune system plays an important role in controlling and eliminating cancer. However, tumors often evade/escape immune attack by modifying their phenotypes and inducing immunosuppression. Recent breakthrough in treating cancers with immune checkpoint inhibitors has fueled the intensive investigation of new therapeutic targets, including negative regulators of adaptive and innate immune systems. We have found that human metastatic melanoma cells spontaneously secrete biologically active interleukin (IL)-1? in the absence of exogenous stimuli because of constitutive activation of IL-1 receptor signaling and a multi-protein complex, ?inflammasome?, exhibiting a feature of ?autoinflammation? (IL-1?-mediated dysregulation of immune system). IL-1? is a pleiotropic pro-inflammatory cytokine and plays a critical role in tumor progression, immunosuppression and chemoresistance. Peripheral blood is an information reservoir and represents systemic processes altered by the presence of tumor cells. We conducted transcriptome profiling of whole blood cells from melanoma patients, and identified differentially expressed genes in human melanoma blood. Of these, we identified a unique cytokine, IL-37, which was highly upregulated in metastatic melanoma blood. IL-37 is a homolog of the IL-1 cytokine family. Dinarello (co-I)?s group has found that IL-37 is a novel inhibitor of innate immunity. PI?s group has found that IL-37 is a novel inhibitor of adaptive immunity. IL-37 is induced in pro-inflammatory milieu containing IL-1. We hypothesize that IL-37 is induced by autoinflammation in human melanoma, leading to tumor-induced immunoevasion. We propose to test this hypothesis using tumor and blood samples from melanoma patients (in Aim 1) and unravel the immunoevasive mechanisms of action of IL-37 in tumor cells (in Aim 2) and blood cells (in Aim 3) in melanoma. The specific aims are: Aim 1: To identify cellular source of IL-37 expression in human melanoma samples and determine the link between IL-37 and autoinflammation in human melanoma. Aim 2: To define biological and mechanistic effects of IL-37 in melanoma cells. Aim 3: To define biological and mechanistic effects of IL-37 in blood cells. IL-37, an inhibitor of innate and adaptive immunity, has not been investigated in tumor immunity. Elucidating the link between autoinflammation and immune escape, and understanding the role of IL-37 in tumor immune escape is critical for clinical success in melanoma and will lead to the development of effective therapeutic agents for cancer.